A large scale virtual screen of DprE1

Wilsey, Claire; Gurka, Jessica; Tóth, Dávid; Franco, Jimmy

doi:10.1016/j.compbiolchem.2013.08.006

Cited by 14 publications

(16 citation statements)

References 21 publications

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“…The primary hit-list consisted of the top 1500 ranked compounds from the high throughput virtual screen (HTVS) of the ZINC Drugs-Now dataset conducted by Vina, a quantity where further refinement and analysis would be achievable. Ranking the initial virtual screen based on docking score alone serves as a starting point in the selection criteria and assumes that the predicted binding affinity somewhat reflects true binding affinity [ 58 , 59 , 60 ]. The lowest binding score within this hit-list corresponded to −9.5 kcal/mol.…”

Section: Resultsmentioning

confidence: 99%

Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study

Berry

Fielding

Gamieldien

2015

Viruses

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Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CLpro provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.

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Section: Resultsmentioning

confidence: 99%

Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study

Berry

Fielding

Gamieldien

2015

Viruses

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“…DprE1 is a dimer characterized by an FAD‐binding domain and the substrate‐binding domain, situated face to face to facilitate the interaction between the substrate and FAD . The active site of DprE1 is bordered by the isoalloxazine ring of FAD .…”

Section: Pbtz169mentioning

confidence: 99%

“…206 DprE1 is a dimer characterized by an FAD-binding domain and the substrate-binding domain, situated face to face to facilitate the interaction between the substrate and FAD. 207 The active site of DprE1 is bordered by the isoalloxazine ring of FAD. 208 The active site of DprE1 is surrounded by positively charged residues to interact with the negatively charged residues of cell membrane where DPR, the natural substrate of this enzyme remains embedded.…”

Section: Interaction Of Pbtz169 With Dpre1mentioning

confidence: 99%

An overview of new antitubercular drugs, drug candidates, and their targets

Bahuguna

Rawat

2019

Medicinal Research Reviews

140

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The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug‐resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four‐drug treatment regimen was introduced 40 years ago but the emergence of multidrug‐resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti‐TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug‐target interactions, and their structure‐activity relationship.

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“…This approach offers the advantage of minimal bench work, and the ability to screen very large compound libraries. For example, 4 million compounds were virtually screened against DprE1 and 41 compounds were identified as likely inhibitors [14]. Six compounds had activity against M. smegmatis suggesting the validity of the approach, although compounds were not tested against M. tuberculosis .…”

Section: Target-based Screening Campaignsmentioning

confidence: 99%

The Future for Early-Stage Tuberculosis Drug Discovery

2015

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There is an urgent need for new and better drugs to treat tuberculosis due to lengthy and complex treatment regimens and a rising problem of drug resistance. Drug discovery efforts have increased over the past few years, with a larger focus on modern high-throughput screening technologies. A combination of target-based approaches, with the traditional empirical means of drug identification, has been complemented by the use of target-based phenotypic screens only recently made possibly with newer genetic tools. Using these approaches, a number of promising compound series have been discovered. However, significant problems remain in developing these into drugs. This review highlights recent advances in TB drug discovery, including an overview of screening campaigns, lessons learned and future directions.

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A large scale virtual screen of DprE1

Cited by 14 publications

References 21 publications

Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study

Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study

An overview of new antitubercular drugs, drug candidates, and their targets

The Future for Early-Stage Tuberculosis Drug Discovery

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